From October 25, 2011, through August 18, 2015, he was the executive vice president and general manager of the Boston Red Sox. He succeeded Theo Epstein in that position, having worked in the team's baseball operations office since 1999, before Epstein's arrival.[2]

Cherington served Boston as an area scout, baseball operations assistant, coordinator of international scouting, and assistant director (and then director) of player development from 1999–2005.[4]

From December 12, 2005, through January 19, 2006, he served as co-general manager of the team with Jed Hoyer during Epstein's absence from the team,[5] with club president/CEO Larry Lucchino and veteran former Major League GM Bill Lajoie also playing key roles during that period. After Epstein's return, Cherington became vice president, player personnel, through January 2009, then senior vice president and assistant GM from 2009 through his promotion to general manager after the 2011 season.[4]

Valentine's 2012 roster included many veterans of the 2011 Red Sox, and he clashed with his players, his holdover coaches, and the media. The team suffered from injuries to key players, struggled out of the gate, improved to a high-water mark of 41–36 (.532) on June 29, but then began to fall back in the standings.[8] When it became clear that the Red Sox would not contend as constituted, Cherington and the team's ownership initiated a trade with the Los Angeles Dodgers on August 25, sending pitcherJosh Beckett, outfielderCarl Crawford and first basemanAdrian Gonzalez — all on expensive, multiyear contracts — to the Dodgers and clearing $262.5 million in salary obligations. Stripped of veteran talent, the 2012 Red Sox went only 9–26 over the final 35 games of the season and finished with their worst record since 1965. Valentine was fired one day after the season ended October 3.[9]

During that offseason, Boston failed to re-sign free agents Ellsbury and Jarrod Saltalamacchia. The 2014 Red Sox, struggling to score runs, fell back to last place in the AL East, losing 26 games from their previous year's standard with a 71–91 record, 25 games behind the division champion Baltimore Orioles. On July 31, with Boston out of the race, Cherington traded starting pitchers Lackey and Jon Lester to contending teams (Peavy had been traded July 26), then retooled the roster during the 2014–15 offseason, adding high-ticket free agents Pablo Sandoval and Hanley Ramírez and trading for starting pitchers Wade Miley and Rick Porcello.

After a promising 12–10 April start to their 2015 season, the Red Sox slumped to a 9–19 May record (scoring the fewest runs in the Major Leagues), and had a horrendous eight-game losing streak after the All-Star break. Porcello, Ramírez and Sandoval performed poorly, the latter two struggling with injuries and illness.

On August 1, with the Red Sox again mired in last place at 47–58, Lucchino announced his intention to retire as president/CEO at the end of the season. Seventeen days later, the Red Sox named veteran MLB executive Dave Dombrowski to the new position of president, baseball operations, to oversee Cherington and the on-field side of the Boston organization. Cherington then turned in his resignation, declining the club's request that he remain as the team's general manager.[12] By that time, only one of the 2013 free agents, injured closer Uehara, remained on the Red Sox' roster. However, Cherington left behind a group of young players (Xander Bogaerts, Mookie Betts, Brock Holt, Eduardo Rodríguez, Blake Swihart, Travis Shaw, Henry Owens, Christian Vázquez, and others) as a potential core of their 2016 team.[13] Five weeks later, Mike Hazen, one of Cherington's assistants, was named his successor.

Although Cherington's name was mentioned as a possible candidate for open general manager posts in MLB, he decided to join Columbia University's Sports Management faculty for the 2015–16 academic year to teach a course in "leadership in sports" during the spring 2016 semester.[14]